Buccal delivery of glucagon-like insulinotropic peptides

ABSTRACT

Drug delivery systems and methods for administering a glucagon-like insulinotropic peptide to the buccal mucosa for transmucosal drug delivery are described. The drug delivery systems comprise a drug composition containing an effective amount of the glucagon-like insulinotropic peptide and an effective amount of a permeation enhancer for enhancing permeation of glucagon-like insulinotropic peptide through the buccal mucosa and means for maintaining the drug composition in a drug transferring relationship with buccal mucosa. These systems can be in free form, such as creams, gels, and ointments, or can comprise a device of determined physical form, such as tablets, patches, and troches. A preferred glucagon-like insulinotropic peptide is GLP-1(7-36)amide.

This application is a continuation of application Ser. No. 08/553,807,filed Oct. 23, 1995 now U.S. Pat. No. 5,766,620.

BACKGROUND OF THE INVENTION

This invention relates to compositions and methods for delivery ofdrugs, especially peptide drugs, to a warm-blooded animal bytransmucosal administration and particularly through the buccal mucosaof the oral cavity. More particularly, the invention relates tocompositions and methods for buccal delivery of glucagon-likeinsulinotropic peptides (GLIPs) into the body.

Traditionally there has been very little work evaluating membranes ofthe oral cavity as sites of drug administration. Both the buccal andsublingual membranes offer advantages over other routes ofadministration. For example, drugs administered through the buccal andsublingual routes have a rapid onset of action, reach high levels in theblood, avoid the first-pass effect of hepatic metabolism, and avoidexposure of the drug to fluids of the gastrointestinal tract. Additionaladvantages include easy access to the membrane sites so that the drugcan be applied, localized, and removed easily. Further, there is goodpotential for prolonged delivery through the buccal membrane. M.Rathbone & J. Hadgraft, 74 Int'l J. of Pharmaceutics 9 (1991).Administration through the buccal mucosa may be better accepted thanrectal dosing, for example, and generally avoids local toxic effects,such as has been a problem in nasal administration. B. Aungst & N.Rogers, 53 Int'l J. Pharmaceutics 227, 228 (1989).

The sublingual route has received far more attention than has the buccalroute. The sublingual mucosa includes the membrane of the ventralsurface of the tongue and the floor of the mouth, whereas the buccalmucosa constitutes the lining of the cheek and lips. The sublingualmucosa is relatively permeable, thus giving rapid absorption andacceptable bioavailabilities of many drugs. Further, the sublingualmucosa is convenient, easily accessible, and generally well accepted.This route has been investigated clinically for the delivery of asubstantial number of drugs. It is the traditional route foradministration of nitroglycerin and is also used for buprenorphine andnifedipine. D. Harris & J. Robinson, 81 J. Pharmaceutical Sci. 1 (1992).The sublingual mucosa is not well suited to sustained-delivery systems,however, because it lacks an expanse of smooth and relatively immobilemucosa suitable for attachment of a retentive delivery system.

The buccal mucosa is less permeable than the sublingual mucosa, and therapid absorption and high bioavailabilities seen with sublingualadministration of drugs is not generally provided to the same extent bythe buccal mucosa. D. Harris & J. Robinson, 81 J. Pharmaceutical Sci. 1,2 (1992). The permeability of the oral mucosae is probably related tothe physical characteristics of the tissues. The sublingual mucosa isthinner than the buccal mucosa, thus permeability is greater for thesublingual tissue. The palatal mucosa is intermediate in thickness, butis keratinized and thus less permeable, whereas the sublingual andbuccal tissues are not keratinized. The buccal mucosa, however, appearswell suited to attachment of retentive delivery systems.

The ability of molecules to permeate through the oral mucosae alsoappears to be related to molecular size, lipid solubility, andionization. Small molecules, less than about 300 daltons, appear tocross the mucosae rapidly. As molecular size increases, however,permeability decreases rapidly. Lipid-soluble compounds are morepermeable through the mucosae than are non-lipid-soluble molecules. Inthis regard, the relative permeabilities of molecules seems to berelated to their partition coefficients. The degree of ionization ofmolecules, which is dependent on the pK_(a) of the molecule and the pHat the membrane surface, also greatly affects permeability of themolecules. Maximum absorption occurs when molecules are unionized orneutral in electrical charge; absorption decreases as the degree ofionization increases. Therefore, charged macromolecular drugs presentthe biggest challenge to absorption through the oral mucosae.

Substances that facilitate the transport of solutes across biologicalmembranes, penetration enhancers, are well known in the art foradministering drugs. V. Lee et al., 8 Critical Reviews in TherapeuticDrug Carrier Systems 91 (1991) hereinafter "Critical Reviews"!.Penetration enhancers can be categorized as (a) chelators (e.g., EDTA,citric acid, salicylates), (b) surfactants (e.g., sodium dodecyl sulfate(SDS)), (c) non-surfactants (e.g., unsaturated cyclic ureas), (d) bilesalts (e.g., sodium deoxycholate, sodium taurocholate), and (e) fattyacids (e.g., oleic acid, acylcarnitines, mono- and diglycerides). Theefficacy of enhancers in transporting both peptide and nonpeptide drugsacross membranes seems to be positively correlated with the enhancer'shydrophobicity. Critical Reviews at 112. For example, the efficacy ofbile salts in enhancing the absorption of insulin through nasalmembranes is positively correlated with the hydrophobicity of the bilesalts' steroid structure. Critical Reviews at 115. Thus, the order ofeffectiveness isdeoxycholate<chenodeoxycholate<cholate<ursodeoxycholate. Conjugation ofdeoxycholate and cholate, but not fusidic acid derivatives, with glycineand taurine does not affect their enhancement potency. Transmucosalintestinal delivery of heparin is not apparent, as measured in terms ofprolongation of partial thromboplastin time or release of plasma lipaseactivity, when administered through the colon of a baboon. However,significant activity is detected when the bile salts, sodium cholate ordeoxycholate, are included in the formulation. Critical Reviews at 108.

Various mechanisms of action of penetration enhancers have beenproposed. These mechanisms of action, at least for peptide and proteindrugs, include (1) reducing the viscosity and/or elasticity of mucuslayer, (2) facilitating transcellular transport by increasing thefluidity of the lipid bilayer of membranes, (3) facilitatingparacellular transport by altering tight junctions across the epithelialcell layer, (4) overcoming enzymatic barriers, and (5) increasing thethermodynamic activity of the drugs. Critical Reviews at 117-125.

Many penetration enhancers have been tested and found effective infacilitating mucosal drug administration, but hardly any penetrationenhanced products have reached the market place. Reasons for thisinclude lack of a satisfactory safety profile respecting irritation,lowering of the barrier function, and impairment of the mucociliaryclearance protective mechanism. Critical Reviews at 169-70. Further, foran enhancer to function adequately, the enhancer and drug combination ispreferably held in position against mucosal tissues for a period of timesufficient to allow enhancer-assisted penetration of the drug across themucosal membrane. In transdermal and transmucosal technology, this isoften accomplished by means of a patch or other device that adheres tothe skin layer by means of an adhesive.

Oral adhesives are well known in the art. See, for example, Tsuk et al.,U.S. Pat. No. 3,972,995; Lowey, U.S. Pat. No. 4,259,314; Lowey, U.S.Pat. 4,680,323; Yukimatsu et al., U.S. Pat. No. 4,740,365; Kwiatek etal., U.S. Pat. No. 4,573,996; Suzuki et al., U.S. Pat. No. 4,292,299;Suzuki et al., U.S. Pat. No. 4,715,369; Mizobuchi et al., U.S. Pat. No.4,876,092; Fankhauser et al., U.S. Pat. No. 4,855,142; Nagai et al.,U.S. Pat. No. 4,250,163; Nagai et al., U.S. Pat. No. 4,226,848;Browning, U.S. Pat. No. 4,948,580; Schiraldi et al.,U.S. Reissue Pat.No. Re.33,093; and J. Robinson, 18 Proc. Intern. Symp. Control. Rel.Bioact. Mater. 75 (1991). Typically, these adhesives consist of a matrixof a hydrophilic, e.g., water soluble or swellable, polymer or mixtureof polymers that can adhere to a wet mucous surface. These adhesives maybe formulated as ointments, thin films, tablets, troches, and otherforms. Often, these adhesives have had medicaments mixed therewith toeffectuate slow release or local delivery of a drug. Some, however, havebeen formulated to permit adsorption through the mucosa into thecirculatory system of the individual.

Glucagon-like insulinotropic peptides, e.g. GLP-1(7-36)amide, areantidiabetogenic agents being investigated for treatment of diabetesmellitus that have heretofore been administered intravenously,subcutaneously, or by some other invasive route, and are too large fortransdermal delivery. Diabetes mellitus afflicts nearly 15 millionpeople in the United States. About 15 percent have insulin-dependentdiabetes (IDDM; type 1 diabetes), which is believed to be caused byautoimmune destruction of pancreatic islet beta cells. In such patients,insulin therapy is essential for life. About 80% of patients havenon-insulin-dependent diabetes (NIDDM; type 2 diabetes), a heterogeneousdisorder characterized by both impaired insulin secretion and insulinresistance. A few patients who appear to have NIDDM may actually have aslowly progressive form of IDDM and eventually become dependent oninsulin. Most patients with NIDDM, however, can be treated withoutinsulin. They are usually overweight and have the insulin resistance ofobesity superimposed on the insulin resistance intrinsic to the disease.Weight loss, especially early in the disease, can restore normal glucoselevels in the blood of these patients. Their diabetes may develop whenthe impact of the combined insulin resistances exceeds the ability oftheir pancreatic beta cells to compensate. Plasma insulin levels in suchpatients, which are often higher than those in people of normal weightwho do not have diabetes, are not appropriate to their obesity andhyperglycemia. People with NIDDM who are not obese may have a primarydefect in insulin secretion in which elevations of plasma glucose levelscause not only insulin resistance but also the further deterioration ofpancreatic beta cell functioning. J. E. Gerich, Oral HypoglycemicAgents, 321 N. Engl. J. Med. 1231 (1989).

NIDDM patients are generally treated with diet modifications andsulfonylureas and/or diguanides. H. E. Lebovitz & M. N. Feinglos,Sulfonylurea Drugs: Mechanism of Antidiabetic Action and TherapeuticUsefulness, 1 Diabetes Care 189 (1978). Oral hypoglycemic agents accountfor about 1 percent of all prescriptions in the United States. J. E.Gerich, 321 N. Engl. J. Med. 1231 (1989). Unfortunately, about 11-36% ofNIDDM patients fail to respond well to diet and sulfonylurea therapyafter one year of treatment. Within 5-7 years, about half of NIDDMpatients receiving sulfonylurea treatment need to start insulin therapy.These patients tend to be resistant to insulin, thus high doses ofinsulin are administered, which in turn leads to hyperinsulinemia whichcan play a role in the development of atherosclerosis. D. A. Robertsonet al., Macrovascular Disease and Hyperinsulinaemia, in Bailliere'sClinical Endocrinology and Metabolism 407-24 (M. Nattras & P. J. Haleeds., 1988).

In warm-blooded animals and humans, GLIPs stimulate insulin release,lower glucagon secretion, inhibit gastric emptying, and enhance glucoseutilization. M. K. Gutniak et al., Antidiabetogenic Effect ofGlucagon-Like Peptide-1 (7-36)amide in Normal Subjects and Patients withDiabetes Mellitus, 326 N. Engl. J. Med. 1316 (1992); D. M. Nathan etal., Insulinotropic Action of Glucagonlike Peptide-1-(7(37) in Diabeticand Nondiabetic Subjects, 15 Diabetes Care 270 (1992); M. A. Nauck etal., Normalization of Fasting Hyperglycaemia by Exogenous GlucagonLikePeptide 1 (7-36 amide) in Type 2 (Non-Insulin-Dependent) DiabeticPatients, 36 Diabetologia 741 (1993). Further, these peptide drugs areinherently safe since the insulinotropic effects are strictly glucosedependent, thus limiting the risk of hypoglycemia in response totherapeutic use thereof. M. A. Nauck et al., Normalization of FastingHyperglycaemia by Exogenous Glucagon-like Peptide 1 (7-36 amide) in Type2 (Non-Insulin-Dependent) Diabetic Patients, 36 Diabetologia 741 (1993).These properties make such peptides serious candidates for a therapeuticdrug in treatment of non-insulin dependent diabetes mellitus (NIDDM).

GLP-1(7-36)amide is a gastrointestinal hormone processed from thepreproglucagon gene. Preproglucagon is a polyprotein hormone precursorcomprising a 20-amino acid signal peptide and a 160-amino acidprohormone, proglucagon (PG). PG has been shown to be processeddifferently in the pancreas and the small intestine of man. C. .Oslashed.rskov et al., Pancreatic and Intestinal Processing ofProglucagon in Man, 30 Diabetologia 874 (1987). In the pancreas, themain products are (a) glucagon (PG amino acids 33-61), (b) aglycentin-related pancreatic peptide (GRPP) (PG amino acids 1-30), and(c) a large peptide-designated major proglucagon fragment (MPGF) (PGamino acids 72-158) that contains two glucagon-like sequences. The onlyproglucagon derived pancreatic peptide with known biological activity isglucagon. In the small intestine, the main products of proglucagon are(a) enteroglucagon (PG amino acids 1-69), which includes the glucagonsequence of amino acids, (b) GLP-1 (PG amino acids 78-107), and (c)GLP-2 (PG amino acids 126-158). C. .O slashed.rskov et al., ProglucagonProducts in Plasma of Noninsulin-dependent Diabetics and NondiabeticControls in the Fasting State and after Oral Glucose and IntravenousArginine, 87 J. Clin. Invest. 415 (1991). A variant of GLP-1(7-36)amide,termed GLP-1(7-37), has been shown to have indistinguishable biologicaleffects and metabolic rates in healthy individuals, D. Gefel et al.,Glucagon-Like Peptide-I Analogs: Effects on Insulin Secretion andAdenosine 3',5'-Monophosphate Formation, 126 Endocrinology 2164 (1990);C. .O slashed.rskov et al., Biological Effects and Metabolic Rates ofGlucagonlike Peptide-1 7-36 Amide and Glucagonlike Peptide-1 7-37 inHealthy Subjects Are Indistinguishable, 42 Diabetes 658 (1993), butGLP-1(7-36)amide is the naturally occurring form in humans, C. .Oslashed.rskov et al., Complete Sequences of Glucagon-like Peptide-1 fromHuman and Pig Small Intestine, 264 J. Biol. Chem. 12826 (1989). It haslong been believed that an endocrine transmitter produced in thegastrointestinal tract, or incretin, stimulates insulin secretion inresponse to food intake. Since GLP-1(7-36)amide is released during ameal and after oral glucose administration and potentiatesglucose-induced insulin release, this peptide may be an importantincretin. J. M. Conlon, Proglucagon-derived Peptides: Nomenclature,Biosynthetic Relationships and Physiological Roles, 31 Diabetologia 563(1988); J. J. Hoist et al., Truncated Glucagon-like Peptide 1, anInsulin-releasing Hormone from the Distal Gut, 211 FEBS Lett. 169(1987); M. Gutniak et al., Antidiabetogenic Effect of Glucagon-likePeptide-1 (7-36)amide in Normal Subjects and Patients with DiabetesMellitus, 326 N. Engl. J. Med. 1316 (1992).

An improved treatment regime for NIDDM patients exhibiting a secondaryfailure to sulfonylurea should give a satisfactory metabolic controlwithout creating marked hyperinsulinemia. Until now, there have been noother serious candidates for a drug that can be used as such atreatment. Glucagon-like insulinotropic peptides, such asGLP-1(7-36)amide, appear to be the most promising treatment of diabetes.J. Eng, U.S. Pat. No. 5,424,286; S. E. Bjorn et al., WO 9517510; J. A.Galloway et al., EP 658568; H. Agerbk et al., WO 9505848; D. E. Danleyet al., EP 619322; G. C. Andrews, WO 9325579; O. Kirk et al., WO9318785; D. I. Buckley et al., WO 9111457; J. F. Habener, U.S.5,118,666; J. F. Habener, WO9011296; J. F. Habener, WO8706941; J. F.Habener, U.S. Pat. No. 5,120,712. It has been found previously that thecombination therapy of a GLIP and a sulfonyl urea exerts a synergisticeffect on glycemia and insulin release. S. Efendic et al., WO 9318786.

R. W. Baker et al., U.S. Pat. No. 5,362,496, disclose oral dosage formsfor transmucosal administration of nicotine for smoking cessationtherapy. Such dosage forms include a lozenge, capsule, gum, tablet,ointment, gel, membrane, and powder, which are typically held in contactwith the mucosal membrane and disintegrate or dissolve rapidly to allowimmediate absorption. J. Kost et al., U.S. Pat. No. 4,948,587, discloseenhancement of transbuccal drug delivery using ultrasound. F. Theeuweset al., U.S. Pat. No. 5,298,017, describes electrotransport of drugs,including peptides, through buccal membrane. J. L. Haslam et al., U.S.Pat. No. 4,478,822, teaches a drug delivery system that can be used forbuccal delivery wherein the drug is combined with a polymer that isliquid at room temperature and semisolid or a gel at body temperature.T. Higuchi et al., U.S. Pat. No. 4,144,317, discloses a shaped body fordrug delivery wherein the drug is contained in an ethylene-vinyl acetatecopolymer. A. Zaffaroni, U.S. Pat. No. 3,948,254, describes buccal drugdelivery with a device having a microporous wall surrounding a closedreservoir containing a drug and a solid drug carrier. The pores containa medium that controls the release rate of the drug.

In view of the foregoing, it will be appreciated that compositions andmethods for prolonged buccal delivery of glucagon-like insulinotropicpeptides, such as GLP-1(7-36)amide, would be significant advancements inthe art.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of the present invention to provide a dosage form andmethod for administering a GLIP that allow easy accessibility to thesite of administration.

It is also an object of the invention to provide a dosage form andmethod for administering a GLIP that promotes high patient acceptanceand compliance.

It is another object of the invention to provide a dosage form andmethod for administering a GLIP that allow for localization of dosageforms over a prolonged period to maximize drug absorption.

It is still another object of the invention to provide a dosage form andmethod for administering a GLIP that provide acceptable tissuecompatibility of the dosage form.

These and other objects are accomplished by providing a drug deliverysystem for transbuccal delivery of a glucagon-like insulinotropicpeptide to an individual's buccal mucosa comprising:

(a) a drug composition comprising an effective amount of a glucagon-likeinsulinotropic peptide and an effective amount of a permeation enhancerfor enhancing permeation of the glucagon-like insulinotropic peptidethrough the buccal mucosa; and

(b) means for maintaining the drug composition in a drug transferringrelationship with the buccal mucosa, wherein the drug composition andthe maintaining means are combined in a single formulation.

The drug delivery system is preferably embodied in either a device ofdetermined physical form, such as a tablet, patch, or troche, or in freeform, such as a gel, ointment, cream, or gum. In preferred devices ofdetermined physical form, such as a tablet or patch, the means formaintaining the drug composition in drug transferring relationship withthe buccal mucosa is an adhesive.

The permeation enhancer is preferably a member selected from the groupconsisting of cell envelope disordering compounds, solvents, steroidaldetergents, bile salts, chelators, surfactants, non-surfactants, fattyacids, and mixtures thereof. A preferred organic solvent is a memberselected from the group consisting of a C₂ or C₃ alcohol, and C₃ or C₄diol, DMSO, DMA, DMF, 1-n-dodecyl-cyclazacyclo-heptan-2-one, N-methylpyrrolidone, N-(2-hydroxyethyl) pyrrolidone, triacetin, propylenecarbonate and dimethyl isosorbide and mixtures thereof. A preferredcell-envelope disordering compound is a member selected from the groupconsisting of isopropyl myristate, methyl laurate, oleic acid, oleylalcohol, glycerol monoleate, glycerol dioleate, glycerol trioleate,glycerol monostearate, glycerol monolaurate, propylene glycolmonolaurate, sodium dodecyl sulfate, and sorbitan esters and mixturesthereof. A preferred bile salt is a steroidal detergent selected fromthe group consisting of natural and synthetic salts of cholanic acid andmixtures thereof.

A preferred tablet according to the invention comprises an adhesivelayer comprising a hydrophilic polymer having one surface adapted tocontact a first tissue of the oral cavity and adhere thereto when wetand an opposing surface in contact with and adhering to an adjacentdrug/enhancer layer comprising the permeation enhancer and theglucagon-like insulinotropic peptide, the drug/enhancer layer adapted tocontact and be in drug transfer relationship with the buccal mucosa whenthe adhesive layer contacts and adheres to the first tissue, preferablythe gingiva. Preferably the hydrophilic polymer comprises at least onemember selected from the group consisting of hydroxypropyl cellulose,hydroxypropyl methylcellulose, hydroxyethylcellulose, ethylcellulose,carboxymethyl cellulose, dextran, gaur-gum, polyvinyl pyrrolidone,pectins, starches, gelatin, casein, acrylic acid polymers, polymers ofacrylic acid esters, acrylic acid copolymers, vinyl polymers, vinylcopolymers, polymers of vinyl alcohols, alkoxy polymers, polyethyleneoxide polymers, polyethers, and mixtures thereof. It is also preferredthat the adhesive layer additionally contain one or more membersselected from the group consisting of fillers, tableting excipients,lubricants, flavors, and dyes and that the drug/enhancer layeradditionally contain one or members selected from the group consistingof tableting excipients, fillers, flavors, taste-masking agents, dyes,stabilizers, enzymer inhibitors, and lubricants. A preferredglucagon-like insulinotropic peptide is GLP-1(7-36)amide. Such a tabletis disclosed and claimed in U.S. Patent Application Serial No. (filed ofeven date herewith).

Another form of bilayer tablet which may suitably be used is disclosedin U.S. Pat. No. 5,346,701.

Another preferred device of determined physical form is a transbuccalpatch, which can be either a matrix patch or a reservoir patch. In apreferred matrix patch, the glucagon-like insulinotropic peptide andpermeation enhancer are suspended or dispersed in the adhesive. In apreferred reservoir patch, the glucagon-like insulinotropic peptide andpermeation enhancer are contained in the reservoir. Typical of suchmatrix and reservoir patches are those illustrated in U.S. Pat. Nos.4,849,224; 4,983,395; 5,122,383; 5,202,125; 5,212,199; 5,227,169;5,302,395 5,346,701.

The drug composition of the present invention can also further comprisean effective amount of a sulfonyl urea.

A method of delivering a glucagon-like insulinotropic peptide fortransbuccal drug delivery to an individual's buccal mucosa comprisesbringing the buccal mucosa into contact with a delivery systemcomprising:

(a) a drug composition comprising an effective amount of theglucagon-like insulinotropic peptide and an effective amount of apermeation enhancer for enhancing permeation of the glucagon-likeinsulinotropic peptide through the buccal mucosa; and

(b) means for maintaining the drug composition in a drug transferringrelationship with the buccal mucosa, wherein the drug composition andthe maintaining means are combined in a single formulation;

and retaining said delivery system in contact with said mucosa for atime sufficient to delivery an effective amount of said peptide to saidindividual.

A method of treating diabetes comprises delivering a glucagon-likeinsulinotropic peptide for transbuccal delivery to an individual'sbuccal mucosa comprising bringing the buccal mucosa into contact with adelivery system comprising:

(a) a drug composition comprising an effective amount of theglucagon-like insulinotropic peptide and an effective amount of apermeation enhancer for enhancing permeation of the glucagon-likeinsulinotropic peptide through the buccal mucosa; and

(b) means for maintaining the drug composition in a drug transferringrelationship with the buccal mucosa, wherein the drug composition andthe maintaining means are combined in a single formulation;

and retaining said delivery system in contact with said mucosa for atime sufficient to delivery an effective amount of said peptide to saidindividual.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a schematic sectional view of a bilayer tablet dosage formaccording to the present invention wherein a drug-containing layerthereof is in drug-transfer relationship with buccal mucosa.

FIG. 2 shows a schematic sectional view of a matrix patch embodimenthaving an optional adhesive overlay according to the present invention.

FIG. 3 shows a schematic sectional view of a liquid reservoir patchaccording to the present invention.

FIG. 4 shows the results of blood glucose determinations for fastingsubjects given a placebo (dotted line) or GLP-1(7-36)amide (solid line)by buccal administration of a bilayer tablet according to the presentinvention.

FIG. 5 shows the results of plasma insulin determinations for subjectsgiven a placebo (O) or GLP-1(7-36)amide () by buccal administration ofa bilayer tablet according to the present invention.

FIG. 6 shows the results of plasma glucagon determinations for subjectsgiven a placebo (O) or GLP-1(7-36)amide () by buccal administration ofa bilayer tablet according to the present invention.

FIG. 7 shows the results of plasma GLP-1(7-36)amide determinations forsubjects given a placebo (dotted line) or the drug (solid line) bybuccal administration of a bilayer tablet according to the presentinvention.

FIG. 8 shows the results of plasma GLP-1 determinations for fastingsubjects given the drug by subcutaneous administration at various doses:(♦) placebo; (▪) 0.15 nmol/kg; (▴) 0.50 nmol/kg; (X) 1.50 nmol/kg; (*)4.50 nmol/kg.

DETAILED DESCRIPTION OF THE INVENTION

Before the present compositions and methods for buccal delivery of aglucagon-like insulinotropic peptide are disclosed and described, it isto be understood that this invention is not limited to the particularformulations, process steps, and materials disclosed herein as suchformulations, process steps, and materials may vary somewhat. It is alsoto be understood that the terminology employed herein is used for thepurpose of describing particular embodiments only and is not intended tobe limiting since the scope of the present invention will be limitedonly by the appended claims and equivalents thereof.

It must be noted that, as used in this specification and the appendedclaims, the singular forms "a," "an," and "the" include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to a bilayer tablet containing "a glucagon-like insulinotropicpeptide" includes a mixture of two or more of such peptides, referenceto "an adhesive" includes reference to one or more of such adhesives,and reference to "a bile salt" includes reference to a mixture of two ormore of such bile salts.

In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions set outbelow.

As used herein, "glucagon-like insulinotropic peptide" or "GLIP" meansinsulinotropic peptides that exhibit substantial amino acid sequencesimilarity to glucagon, such as GLP-1(7-36)amide and precursors,analogues, and fragments thereof wherein said precursors, analogues, andfragments have insulinotropic, or insulin stimulating, activity. Suchprecursors, analogues, and fragments include polypeptides having theprimary sequence of GLP-1(7-36)amide wherein one or more L-amino acidresidues are coupled to the C-terminus or N-terminus thereof, e.g.GLP-1(7-37); wherein the C-terminus contains a carboxyl group, an amideor substituted amide, an ester, or salt; and combinations thereof. Alsoincluded in the definition are peptides substantially homologous toGLP-1(7-36)amide and analogues thereof, provided such homologouspeptides also contain insulinotropic activity. As used herein,"substantially homologous" refers to peptides that retain functionalitydespite differences in primary structure from peptides to which they arecompared. For example, a peptide substantially homologous toGLP-1(7-36)amide is one that retains functionality as an insulinotropicagent although it may include additional amino acid residues or be atruncation, deletion variant, or substitution variant thereof. Asubstitution variant is one that contains a conservative substitution ofone or more amino acid residues. A conservative substitution is asubstitution of one amino acid residue for another wherein functionalityof the peptide is retained, in this case, functionality as aninsulinotropic agent. Amino acid residues belonging to certainconservative substitution groups can sometimes substitute for anotheramino acid residue in the same group. One such classification ofconservative substitution groups is as follows: (a) Pro; (b) Ala, Gly;(c) Ser, Thr; (d) Asn, Gln; (e) Asp, Glu; (f) His; (g) Lys, Arg; (h)Cys; (i) Ile, Leu, Met, Val; and (j) Phe, Trp, Tyr. M. Jimenez-Montano &L. Zamora-Cortina, Evolutionary model for the generation of amino acidsequences and its application to the study of mammal alpha-hemoglobinchains, Proc. VIIth Int'l Biophysics Congress, Mexico City (1981).Another such classification is described in M. Dayhoff et al., Atlas ofProtein Sequence and Structure 1978 (Nat'l Biomed. Res. Found.,Washington, D.C.), hereby incorporated by reference. Other variationsthat are to be considered substantially homologous include substitutionof D-amino acids for the naturally occurring L-amino acids, substitutionof amino acid derivatives such as those containing additional sidechains, and substitution of non-standard amino acids, i.e. α-amino acidsthat are rare or do not occur in proteins. The primary structure of asubstantially homologous peptide is thus limited only by functionality.

As used herein, "peptide" means peptides of any length and includesproteins. The terms "polypeptide" and "oligopeptide" are used hereinwithout any particular intended size limitation, unless a particularsize is otherwise stated.

As used herein, "chemical enhancer," "penetration enhancer," "permeationenhancer," and the like shall be inclusive of all enhancers thatincrease the flux of a permeant, drug, or other molecule across themucosa and is limited only by functionality. In other words, all cellenvelope disordering compounds, solvents, steroidal detergents, bilesalts, chelators, surfactants, non-surfactants, fatty acids, and anyother chemical enhancement agents are intended to be included.

The flux of a drug or analyte across the mucosa can be increased bychanging either the resistance (the diffusion coefficient) or thedriving force (the gradient for diffusion) Flux may be enhanced by theuse of so-called penetration or permeation or chemical enhancers.

Permeation enhancers are comprised of two primary categories ofcomponents, i.e., cell-envelope disordering compounds and solvents orbinary systems containing both cell-envelope disordering compounds andsolvents. As discussed above, other categories of permeation enhancerare known, however, such as steroidal detergents, bile salts, chelators,surfactants, non-surfactants, and fatty acids.

Cell envelope disordering compounds are known in the art as being usefulin topical pharmaceutical preparations and function also in drugdelivery through the skin or mucosa. These compounds are thought toassist in dermal penetration by disordering the lipid structure of thestratum corneum cell-envelopes. A list of such compounds is described inEuropean Patent Application 43,738, published Jun. 13, 1982, which isincorporated herein by reference. It is believed that any cell envelopedisordering compound is useful for purposes of this invention. Exemplaryof the cell envelope disordering compounds are those represented by theformula:

    R-X

wherein R is a straight-chain alkyl of about 7 to 16 carbon atoms, anon-terminal alkenyl of about 7 to 22 carbon atoms, or a branched-chainalkyl of from about 13 to 22 carbon atoms, and X is --OH, --COOCH₃,--COOC₂ H₅, --OCOCH₃, --SOCH₃, --P(CH₃)₂ O, --COOC₂ H₄ OC₂ H₄ OH,--COOCH(CHOH)₄ OH₂ OH, --COOCH₂ CHOHCH3, --COOCH₂ CH(OR")CH₂ OR",--(OCH₂ CH₂)_(m) OH, --COOR', or --CONR'₂ where R' is --H, --CH₃, --C₂H₅, --C₃ H₇ or --C₂ H₄ OH; R" is --H, or a non-terminal alkenyl of about7 to 22 carbon atoms; and m is 2-6; provided that when R" is an alkenyland X is --OH or --COOH, at least one double bond is in thecis-configuration.

Suitable solvents include water; diols, such as propylene glycol andglycerol; mono-alcohols, such as ethanol, propanol, and higher alcohols;DMSO; dimethylformamide; N,N-dimethylacetamide; 2-pyrrolidone;N-(2-hydroxyethyl) pyrrolidone, N-methylpyrrolidone,1-dodecylazacycloheptan-2-one and othern-substituted-alkyl-azacycloalkyl-2-ones (azones) and the like.

U.S. Pat. No. 4,537,776, Cooper, issued Aug. 27, 1985, contains anexcellent summary of prior art and background information detailing theuse of certain binary systems for permeant enhancement. Because of thecompleteness of that disclosure, the information and terminologyutilized therein are incorporated herein by reference.

Similarly, European Patent Application 43,738, referred to above,teaches using selected diols as solvents along with a broad category ofcell-envelope disordering compounds for delivery of lipophilicpharmacologically-active compounds. Because of the detail in disclosingthe cell-envelope disordering compounds and the diols, this disclosureof European Patent Application 43,738 is also incorporated herein byreference.

A binary system for enhancing metoclopramide penetration is disclosed inUK Patent Application GB 2,153,223 A, published Aug. 21, 1985, andconsists of a monovalent alcohol ester of a C8-32 aliphaticmonocarboxylic acid (unsaturated and/or branched if C18-32) or a C6-24aliphatic monoalcohol (unsaturated and/or branched if C14-24) and anN-cyclic compound such as 2-pyrrolidone, N-methylpyrrolidone and thelike.

Combinations of enhancers consisting of diethylene glycol monoethyl ormonomethyl ether with propylene glycol monolaurate and methyl laurateare disclosed in U.S. Pat. No. 4,973,468 as enhancing the transdermaldelivery of steroids such as progestogens and estrogens. A dual enhancerconsisting of glycerol monolaurate and ethanol for the transdermaldelivery of drugs is shown in U.S. Pat. No. 4,820,720. U.S. Pat. No.5,006,342 lists numerous enhancers for transdermal drug administrationconsisting of fatty acid esters or fatty alcohol ethers of C₂ to C₄alkanediols, where each fatty acid/alcohol portion of the ester/ether isof about 8 to 22 carbon atoms. U.S. Pat. No. 4,863,970 showspenetration-enhancing compositions for topical application comprising anactive permeant contained in a penetration-enhancing vehicle containingspecified amounts of one or more cell-envelope disordering compoundssuch as oleic acid, oleyl alcohol, and glycerol esters of oleic acid; aC₂ or C₃ alkanol and an inert diluent such as water.

Other permeation enhancers, not necessarily associated with binarysystems include DMSO or aqueous solutions of DMSO such as taught inHerschler, U.S. Pat. No. 3,551,554; Herschler, U.S. Pat. No. 3,711,602;and Herschler, U.S. Pat. 3,711,606, and the azones(n-substituted-alkyl-azacycloalkyl-2-ones) such as noted in Cooper, U.S.Pat. No. 4,557,943.

As used herein, "bile salts" means the steroidal detergents that are thenatural or synthetic salts of cholanic acid, e.g. the salts of cholicand deoxycholic acid or combinations of such salts, and the unionizedacid form is also included. The salts of the conjugates of the bile acidwith glycine or taurine are preferred, with the taurine salts beingparticularly preferred. Bile salt analogs having the same physicalcharacteristics and that also function as permeation enhancers are alsoincluded in this definition. "NaTC" is the bile salt, sodiumtaurocholate. "CHAPS" is the bile salt analog, 3-3-cholamidopropyl)dimethylammonio!-1-propane sulfate, inner salt.

As used herein, "transmucosal," "transbuccal," and similar terms meanpassage of a glucagon-like insulinotropic peptide into and through thebuccal mucosa to achieve effective therapeutic blood levels or deeptissue levels thereof.

As used herein, "effective amount" means an amount of a glucagon-likeinsulinotropic peptide that is nontoxic but sufficient to provide aselected systemic effect and performance at a reasonable benefit/riskratio attending any medical treatment. An effective amount of apermeation enhancer, as used herein, means an amount selected so as toprovide the selected increase in mucosal permeability and,correspondingly, the desired depth of penetration, rate ofadministration, and amount of drug delivered.

As used herein, "adhesive," "adhesive polymer", "mucoadhesive", or suchsimilar terms refers to hydrophilic polymers, natural or synthetic,which, by the hydrophilic designation, can be either water soluble orswellable and which are compatible with the enhancers and glucagon-likeinsulinotropic peptides. Such adhesives function for adhering the dosageforms to the mucous tissues of the oral cavity, such as the gingiva.Such adhesives are inclusive of hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxy ethylcellulose, ethylcellulose, carboxymethylcellulose, dextran, gaur gum, polyvinyl pyrrolidone, pectins, starches,gelatin, casein, acrylic acid polymers, polymers of acrylic acid esters,acrylic acid copolymers, vinyl polymers, vinyl copolymers, polymers ofvinyl alcohols, alkoxy polymers, polyethylene oxide polymers,polyethers, and mixtures thereof, and the like.

By "system", "drug delivery system", "transmucosal delivery system" orthe like is meant a unit dosage form of a drug composition, includingcarriers, enhancers, and other components, which drug composition iscontained in or accompanied by means for maintaining the drugcomposition in a drug transferring relationship with the buccal mucosa.Such means can be either a patch, tablet, troche, or other device ofdetermined physical form to be held against the buccal mucosa forcontinuous drug administration thereto for systemic transport, or suchmeans can be formulated in free form to be applied directly to thebuccal mucosa as a cream, gel, gum, ointment and the like. The term"troche" includes pastille, lozenge, morsulus, rotula, trochiscus, andthe like. "Free form" means that the formulation is spreadable ormalleable into a selected shape at the time of application. "Determinedphysical form" means that the formulation has a form determined by adevice. Preferably the means used will be a device such as a tablet ormatrix or liquid reservoir patch. A matrix patch contains the drug,permeation enhancer, and other optional ingredients suspended ordispersed in an adhesive layer. A reservoir patch contains the drug,permeation enhancer, and other optional ingredients in a reservoir,which can be in liquid form, or the liquid can be gelled or thickened byan agent such as mineral oil, petroleum jelly and various aqueousgelling agents and hydrophilic polymers. Such a reservoir or matrixpatch is brought into contact with the buccal mucosa and is held inplace by a suitable adhesive. In a reservoir patch, the drug compositionis applied to the buccal mucosa through a permeable membrane forming thereservoir floor that is in direct contact with the buccal mucosa.

The method of application of the present invention can vary withinlimits, but necessarily involves applying the selected drug compositionto the buccal mucosa such that drug delivery is initiated and continuesfor a period of time sufficient to provide the selected pharmacologicalor biological response.

Bilayer Tablets for Delivery of GLIP Referring to FIG. 1 there is shownan illustrative dosage form according to the present invention foradministering GLIP through the buccal mucosa. This dosage form isprovided as a bilayer tablet 10 such that drug/adhesive interactionsthat inhibit efficient transmembrane flux of GLIP through the mucosaltissue are greatly diminished or eliminated. The bilayer tablet 10comprises an adhesive layer 12 and an active or drug-containing layer14. The adhesive layer 12 is formulated to adhere to a mucous surface inthe oral cavity such that the active layer 14 is in a drug-transferrelationship with a mucosal tissue, such as the buccal mucosa, such thatthe drug permeates through the mucosal tissue and is absorbed into thebloodstream of the individual. In the illustrative embodiment of FIG. 1,the tablet 10 is placed in the oral cavity such that the adhesive layer12 adheres to a gingival (keratinized) surface 16 and the active layer14 is in drug-transfer relationship with the buccal mucosa 18.

Bilayer tablets are made by classical bilayer tablet compressiontechniques on a suitable press. In reference to FIG. 1, the bilayertablets 10 consist of an adhesive layer 12 and an active ordrug-containing layer 14, which can be of a different color todistinguish the layers for purposes of application. The identificationof the drug-containing, non-adhesive layer 14 facilitates application bythe patient and prevents incidental adhesion of other oral tissues tothe tablet. The adhesive layer 12 is prepared by either dry mixing theingredients and compressing them into a tablet or by wet granulating theingredient mixture and then compressing according to acceptedpharmaceutical techniques. In general, it has been found suitable to mixthe adhesive polymer or polymers and any formulation aids such asfillers, tableting excipients, lubricants, flavors, dyes, and the likeand then compress the mixture in a press.

The drug-containing or active layer 14 is first prepared by intimatelyadmixing the drug with a permeation enhancer and any other formulationaids such as tableting excipients, dyes, flavors, taste-masking agents,stabilizers, enyzmer inhibitors, lubricants, and the like. This can beformulated as a dry mix or accomplished by conventional wet granulationand screening techniques followed by drying. In either event, theblended drug-containing layer ingredients are then placed on top of thepartially compressed adhesive layer and both layers are then compressed.A person of ordinary skill in the art will recognize that the instanttablet can also be manufactured by making the drug-containing layerfirst and then the adhesive layer.

The compositions of the present invention will preferably be sized toprovide between about 0.05 to 10 cm² of surface area for contact betweenthe drug-containing layer and the mucosa. Areas of between about 0.07 to5 cm² are preferred with areas of between about 0.18 and 5 cm² beingoptimal. The drug-containing or active layer will generally have athickness of between about 0.1 and 3 mm with thicknesses of betweenabout 0.5 and 2 mm being preferred.

The following examples are illustrative of methods of preparing bilayertablets according to the present invention.

EXAMPLE 1

Bilayer tablets are prepared in the following manner. An adhesive layerwas prepared by weighing 70 parts by weight polyethylene oxide (Polyox301N; Union Carbide), 20 parts by weight polyacrylic acid (Carbopol934P; B.F. Goodrich), and 10 parts by weight of a compressiblexylitol/carboxymethyl cellulose filler (Xylitab 200; Xyrofin). Theseingredients were mixed by rolling in a jar for 3 minutes. The mixturewas then transferred to an evaporating dish and quickly wet granulatedwith absolute ethanol to a semi-dough-like consistency. This mass wasimmediately and rapidly forced through a 14 mesh (1.4 mm opening)stainless steel screen, to which the wet granules adhered. The screenwas covered with perforated aluminum foil, and the wet granules weredried overnight at 30° C. The dried granules were removed from thescreen and then passed through a 20 mesh (0.85 mm opening) screen tofurther reduce the size of the granules. Particles that did not passthrough the 20 mesh screen were ground briefly with a mortar and pestleto minimize the amount of fines and then passed through the 20 meshscreen. The resulting granules were then placed in a mixing jar, and0.25 parts by weight stearic acid and 0.06 parts by weight mint flavor(Universal Flavors) were added and blended to the granules. The finalpercentages by weight of the ingredients were thus 69.78% polyethyleneoxide, 9.97% compressible xylitol/carboxymethyl cellulose filler, 19.94%polyacrylic acid, 0.25% stearic acid, and 0.06% mint flavor. A 50 mgamount of this mixture was placed on a 0.375 inch diameter die andprecompressed on a Carver Press Model C with 0.25 metric ton pressurefor a 3 second dwell time to form the adhesive layer.

The active layer was prepared by weighing 49.39 parts by weight ofmannitol, 34.33 parts by weight of hydroxypropyl cellulose (Klucel L F;Aqualon, Wilmington, Del.) and 15.00 parts by weight of sodiumtaurocholate (Aldrich, Milwaukee, Wis.), and mixing by rolling in a jarfor 3 minutes. The mixture was then transferred to an evaporating dishand quickly wet granulated with absolute ethanol to a semi-dough-likeconsistency. This mass was immediately and rapidly forced through a 14mesh stainless steel screen, to which the wet granules adhered. Thescreen was covered with perforated aluminum foil, and the granules weredried at 30° C. The dried granulation was then passed sequentiallythrough 20, 40 (0.425 mm opening), and 60 (0.25 mm opening) mesh screensto reduce particle size further. Particles that did not pass through ascreen were briefly ground with a mortar and pestle to minimize finesand then passed through the screen. The screened particles were weighed,and then 0.91 parts by weight of GLP-1(7-36)amide and 0.06 parts byweight of FD&C yellow #6HT aluminum lake dye were sequentially blendedwith the dry granulation by geometric dilution. The dyed granulation wasthen placed in a mixing jar and blended with 0.25 parts by weightmagnesium stearate (lubricant) and 0.06 parts by weight mint flavor byrolling for 3 minutes. A 50 mg sample of this material was placed on topof the partially compressed adhesive layer and both layers were thencompressed at 1.0 ton pressure for a 3 second dwell time to yield abilayer tablet suitable for buccal delivery.

This procedure results in a gingival tablet wherein the active layercontains 0.91% by weight of GLP-1(7-36)amide, 15% by weight of NaTC, and84.09% by weight of filler, lubricant, colorant, formulation aids, orflavoring agents.

EXAMPLE 2

The procedure of Example 1 was followed with the exception that theamounts of the components of the active layer were varied to provide anactive layer containing 65.30% by weight mannitol, 34.33% hydroxypropylcellulose, 0.25% magnesium stearate, 0.06% FD&C yellow #6HT aluminumlake dye, and 0.06% mint flavor. This procedure results in placebotablets suitable for use in double-blind in vivo studies with humanvolunteers.

EXAMPLE 3

The procedure of Example 1 was followed to prepare a buccal tabletwherein the active layer contained the same content but was prepared bydry blending and not by wet granulation.

Buccal Patch for Delivery of GLIP

FIG. 2 shows an illustrative filmpatch embodiment for buccal delivery ofGLIP wherein the patch 20 consists of an underlyingdrug/enhancer/polymer layer 21 and an outer inert membrane layer 22having the same diameter as active layer 21. However, the outer inertlayer of a patch may extend beyond the outer periphery of the underlyingactive layer and have contained on the under surface thereof, additionalmucoadhesive (not shown) or, as shown in FIG. 2, there may be anoptional overlay 23 containing a mucoadhesive on the inner surface ofoverlay 23 which extends beyond the outer periphery of both the activelayer 21 and the inert membrane layer 22. In this manner, the active orinner layer is completely surrounded by the overlying membrane whichadheres to the mucosa and further insures that the drug/enhancercombination will remain in the area of the oral mucosa in which it isapplied until the drug/enhancer portions of the layer have beenadequately delivered. The optional overlay 23 may also be aperm-selective membrane having a desired molecular weight cutoff (MWCO)pore structure. In certain instances it may be beneficial to have bothmembrane 22 and overlay 23 both be MWCO membranes, each having adifferent MWCO value for controlling or varying the amount or degree ofwater or other materials passing through such membranes.

FIG. 3 shows an illustrative liquid reservoir patch that can be usedaccording to the present invention for delivering a glucagon-likeinsulinotropic peptide to the buccal mucosa. This liquid reservoir patchis described in U.S. Pat. No. 4,849,224, hereby incorporated byreference. As described in that patent, such devices, shown generally at24 in FIG. 3 are comprised of an uppermost layer of a heat-sealablebacking film 26 having an inverted, cup-shaped recess that serves as thereservoir 28 for the drug composition. The underside of the outer edgeof the backing film carries a ring-shaped layer 30 of an adhesiveperipheral to the reservoir. Underlying the reservoir, just inward ofthe peripheral ring of adhesive is a membrane layer 32 that is permeableto the drug composition. A peel sealable inner liner 34 underliesmembrane 32 and portions of backing film 26. A peel-sealable releaseliner 36 covers the entire underside of the assembly and forms the basalsurface of the device. Device 18 has a heat seal 38 between the membraneand backing film. An alternative liquid reservoir-type device that canbe used in conjuction with the present invention is described in U.S.Pat. No. 4,983,395, hereby incorporated by reference.

EXAMPLE 4

A buccal patch formulation is prepared containing 400 μg ofGLP-1(7-36)amide using a 500 MWCO dialysis membrane as the outercovering or layer. To a vial are added 278.3 μl of a 30% by weight NaTCaqueous solution and 59 μl of 1.2% by weight GLP-1(7-36)amide aqueoussolution. The solutions are stirred together until a clear solution isformed. To this is added an ethanol solution containing 1130.8 μl of19.85% hydroxypropyl cellulose with stirring until a homogeneous mixtureis obtained. A 718 μl portion of this mixture is then cast onto a 500MWCO dialysis membrane, which has been dried in an oven at 70° C. toprovide a dry substrate, in a glass mold and allowed to dry overnight.Excess membrane is trimmed from around the translucent homogeneousactive layer to yield a finished buccal patch having a surface area ofabout 5 cm². The active layer of this patch contains 400 μg ofGLP-1(7-36)amide (4.8% by weight), 45 mg of NaTC (15% by weight), and100.4 mg of hydroxypropyl cellulose (34% by weight)

EXAMPLE 5

Troche for Delivery of GLIP

A troche for buccal delivery of a glucagon-like insulinotropic peptideis made by incorporating 400 μg of GLP-1(7-36)amide, in a mass made of asugar and mucilage and also containing 15% by weight of NaTC, and thenair drying the mixture as is well known in the art of making troches.

EXAMPLE 6

Free Form Dosage Form for Delivery of GLIP

A dosage form in free form for delivery of a glucagon-likeinsulinotropic peptide is made by incorporating 400 μg ofGLP-1(7-36)amide in a liquid mixture comprising about 15% by weight ofNaTC, and 85% by weight of water. To 12 ml of this mixture was added0.15 g of Carbopol 1342 acrylic acid copolymer. This mixture washomogenized to result in a gelled drug composition.

In Vivo Testing of GLIP Delivery

EXAMPLE 7

This example describes a double-blind, placebo-controlled, crossovercomparison with random assignment to treatment sequence. Eight healthyvolunteers were selected for this in vivo study of blood glucose,insulin, glucagon, and GLP-1(7-36)amide levels in response to receivingeither a drug-containing bilayer tablet containing 400 μg ofGLP-1(7-36)amide or a placebo prepared according to Examples 1 and 2,respectively. Inclusion criteria for the volunteers were normal glucosetolerance, weight within 22<BMI<26, informed consent to participate inthe study, and age between 20 and 60 years. Exclusion criteria wereimpaired glucose tolerance (2-hour glucose tolerance test; OGTT),gastrointestinal symptoms, ongoing medication or illness, acuteinfection, abnormal laboratory variables (hemoglobin, hematocrit,leucocytes, creatinine, bilirubin, calcium, potassium, sodium, alkalinephosphatase, gamma-GT, SGOT, SGPT, cholesterol, and triglycerides) , andblood pressure greater than 185 mmHg systolic and/or 90 mmHg diastolic.

Subject numbers were allotted to the subjects in the order in which theywere enrolled in the study. The number allotted to each subjectdetermined the treatment sequence received. Subjects receiving treatmentsequence 1 were treated with drug followed by placebo, and subjectsreceiving treatment sequence 2 were treated with placebo followed bydrug.

Subjects were instructed to fast the night before a treatment. At theclinic, the subjects were given either a drug-containing bilayer tabletor placebo. At time 0 the bilayer tablet was applied to the gingiva withthe active layer i contact with the tissue of the lip or inside of thecheek, and the subjects were placed in a rest position. The bilayertablet was removed after 4.5 hours. No meals were allowed until astandard meal was given after 4.5 hours, and snacks were not permittedat any time. The standard meal contained 550 kcal, with 28%, 22%, and50% of the energy from protein, fat, and carbohydrate, respectively. Thetest continued until 8 hours after application of the bilayer tablet,and the subjects left the hospital after 9 hours. The subjects weregiven their medications in the clinic by a nurse and were underobservation at all times. Any symptoms or sensations disturbing orimpairing the subjects' wellbeing during the experiments was carefullydocumented. Standard safety variables were determined under fastingconditions before each experiment. Blood glucose was monitoredfrequently and glucose infusion was available in case of hypoglycemia(<2.5 mmol/L). If any subject were to experience hypoglycemic symptoms,an extra blood glucose determination would be taken for safety reasons.A washout period of 1-4 days was allowed between each experiment. Thestudy was completed within 6 weeks after enrollment of the firstvolunteer.

Blood samples were taken for pharmacokinetic analysis 10 minutes beforeapplication of the drug, and at 5, 10, 15, 20, 25, 30, 40, 50, 60, 75,90, 120, 150, 180, 210, 240, and 270 minutes and 6 and 8 hours afterapplication of the drug. Samples were frozen until assayed forGLP-1(7-36)amide content by double antibody radioimmunoassay (RIA). Thepeptide content of bilayer tablet samples was also analyzed by HPLC.Average blood glucose, insulin, glucagon, and GLP-1(7-36)amideconcentrations were calculated by area under the curve (AUC) using thetrapezoidal rule. The maximal concentration (C_(max)) , half-life(T_(1/2)), and time to maximal blood level (T_(max)) were calculated forGLP-1(7-36)amide based on plasma levels of the peptide. Results weretested for normal distribution. A two-tailed t-test was carried out fornormally distributed samples, and a Wilcoxon rank-sum test was used fordata that were not normally distributed. All statistical tests used alevel of significance of 0.05.

FIG. 4 shows the results of blood glucose determinations for subjectsgiven the placebo (dotted line) or drug (solid line). For the placebogroup, blood glucose levels remain relatively constant from 10 minutesbefore application of the bilayer tablet through 270 minutes afterapplication thereof. Over the same time period, the blood glucose levelsof subjects receiving GLP-1(7-36)amide drop below that of the placebogroup by 20 minutes after application of the drug, reach a lowest levelof about 3 mmol/L at about 50 minutes, and return to a normal level byabout 90 minutes. Blood glucose levels of the two groups areindistinguishable after the meal. These data show that buccaladministration of GLP-1(7-36)amide with the bilayer tablet according tothe present invention results in significantly reduced blood glucoselevels as compared to placebo controls.

FIG. 5 shows the results of plasma insulin determinations for subjectsgiven the placebo (O) or the drug (). For the placebo group, the plasmainsulin levels remain relatively constant or decline slightly over thecourse of 10 minutes prior to administration of the bilayer tablet to270 minutes after administration thereof. For the group receiving GLP-1,the plasma insulin level rises sharply from a normal level at 10 minutesafter administration of the drug to a level about three time normal at15 minutes after administration. A peak plasma insulin level is reachedabout 20 minutes after administration of GLP-1(7-36)amide, and the levelrapidly declines to normal by about 50 minutes. Otherwise, the insulinlevels of the drug group track the insulin levels of the placebo group.Thus, buccal administration of GLP-1(7-36)amide results in a rapidincrease of plasma insulin concentration followed by a rapid decrease,both within an hour of administration of the drug.

FIG. 6 shows the results of plasma glucagon determinations for subjectsgiven the placebo (O) or the drug (). For the placebo group, the plasmaglucagon level declines slowly and steadily from 10 minutes prior toadministration of the bilayer tablet until 270 minutes afteradministration thereof. For the drug group, the plasma glucagon leveldeclines sharply from time 0 until a level significantly lower than theplacebo group is reached about 30 minutes later, and then the levelrises sharply to a level significantly higher than the placebo group,reaching a peak about 60-75 minutes after administration. From thispeak, the plasma glucagon level declines steadily until it tracks thelevel of the placebo group beginning at about 150 minutes afteradministration of the drug. These data show that buccal administrationof GLP-1(7-36)amide quickly lowers plasma glucagon levels below those ofthe placebo group and then raises them to higher than normal levelsbefore they reach normal levels again about 150 minutes afteradministration.

FIG. 7 shows the results of plasma GLP-1(7-36)amide determinations forsubjects given the placebo (dotted line) or drug (solid line). For theplacebo group, the amount of GLP-1(7-36)amide in the plasma remainsfairly constant at a very low level from 10 minutes prior toadministration of the drug until 270 minutes after administrationthereof. After the meal, the plasma GLP-1(7-36)amide level rises andthen declines steadily over time. For the drug group, the plasmaGLP-1(7-36)amide level rises sharply beginning within 5 minutes ofadministration and reaches a peak about 30 minutes after administration.The GLP-1(7-36)amide level then declines rapidly until about 90 minutesafter administration, and then declines more slowly to a level thattracks that of the placebo group beginning at about 150 minutes. Afterthe meal, the GLP-1(7-36)amide level is approximately the same as thatof the placebo group. These results show that buccal administration ofGLP-1(7-36)amide results in rapid absorption through the buccal mucosainto the bloodstream and that elevated levels of GLP-1(7-36)amide remainin the blood until about 150 minutes after administration.

Taken together, these data show that buccal administration ofGLP-1(7-36)amide with the bilayer tablet of the instant inventionresults in rapid absorption into the bloodstream that leads to a sharprise in the amount of plasma insulin and a corresponding decrease in theamount of glucose in the blood. Further, the blood glucose level doesnot result in hypoglycemia, probably because of the above-mentionedglucose dependence of the insulinotropic effects of the drug.

EXAMPLE 8

In this example, the relative bioavailability of GLP-1(7-36)amide bybuccal administration is compared to that of subcutaneously administeredGLP-1. This was done in comparison to published data. Two studiesproviding intravenous infusion data in fasting individuals areavailable: D. M. Nathan et al., Insulinotropic Action of Glucagonlikepeptide-1-(7-37) in Diabetic and Nondiabetic Subjects, 15 Diabetes Care270 (1992); C. .O slashed.rskov et al., Biological Effects and MetabolicRates of Glucagonlike Peptide-1 7-36 amide and Glucagonlike Peptide-17-37 in Healthy Subjects is Indistinguishable, 42 Diabetes 658 (1993).Both of these studies support an approximate clearance of 15 ml/min/kg.

A study by M. A. Nauck of subcutaneous administration of GLP-1 tofasting subjects illustrates changes in the pharmocokinetics with dose(FIG. 8). This could be due to changes in bioavailability with dose,changes in clearance with dose, or a combination of both effects. At anyrate, regression analysis of all the results indicate a clearance ofabout 40 ml/min/kg, which is consistent with a bioavailability of 38% bysubcutaneous administration relative to intravenous administration.

The data summarized in FIG. 7 were analyzed by AUC to provide anestimate of relative bioavailability by buccal administration ascompared to subcutaneous administration. These data are shown in Table1.

                  TABLE 1    ______________________________________    GLP-1(7-36)amide Pharmacokinetic Summary - Buccal Delivery          Dose    AUC        Dose  Bioavail-                                          Half-Life    Subject          (nmol)  (pmol-min/L)                             (nmol)                                   ability (%)                                          (30-210 min)    ______________________________________    901   119     9113       9.57  8.04   27.13    902   119     7256       7.61  6.40   23.99    903   119     8753       9.19  7.72   29.49    904   119     --         --    --     --    905   119     8410       8.83  7.42   18.80    906   119     11343      11.91 10.01  24.38    907   119     3278       3.44  2.89   29.95    908   119     --         --    --     --    Mean  119     8024       8.43  7.08   25.62    SD            2683       2.82  2.37    4.17    ______________________________________

These data show a relative bioavailability of 27% as compared to thedata of FIG. 8.

We claim:
 1. A drug delivery system for transbuccal delivery of aglucagon-like insulinotropic peptide to an individual's buccal mucosacomprising:(a) a drug composition comprising an effective amount of aglucagon-like insulinotropic peptide and an effective amount of apermeation enhancer for enhancing permeation of said glucagon-likeinsulinotropic peptide through said buccal mucosa; and (b) means formaintaining said drug composition in a drug transferring relationshipwith said buccal mucosa, wherein said drug composition and saidmaintaining means are combined in a single formulation.
 2. The drugdelivery system of claim 1 wherein said system comprises a device ofdetermined physical form.
 3. The drug delivery system of claim 2 whereinsaid device of determined physical form is a member selected from thegroup consisting of a patch and a tablet, and wherein said maintainingmeans is an adhesive.
 4. The drug delivery system of claim 3 whereinsaid permeation enhancer is a member selected from the group consistingof cell envelope disordering compounds, solvents, steroidal detergents,bile salts, chelators, surfactants, non-surfactants, fatty acids, andmixtures thereof.
 5. The drug delivery system of claim 4 wherein saiddevice of determined physical form is a tablet.
 6. The drug deliverysystem of claim 5 wherein said tablet comprises an adhesive layercomprising a hydrophilic polymer having one surface adapted to contact afirst tissue of the oral cavity and adhere thereto when wet and anopposing surface in contact with and adhering to an adjacentdrug/enhancer layer comprising said permeation enhancer and saidglucagon-like insulinotropic peptide, said drug/enhancer layer adaptedto contact and be in drug transfer relationship with said buccal mucosawhen said adhesive layer contacts and adheres to said first tissue. 7.The drug delivery system of claim 6 wherein said permeation enhancercomprises a bile salt, wherein said bile salt is a steroidal detergentselected from the group consisting of natural salts of cholanic acid,synthetic salts of cholanic acid, and mixtures thereof.
 8. The drugdelivery system of claim 7 wherein said hydrophilic polymer comprises atleast one member selected from the group consisting of hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose,ethylcellulose, carboxymethyl cellulose, dextran, gaur-gum, polyvinylpyrrolidone, pectins, starches, gelatin, casein, acrylic acid polymers,polymers of acrylic acid esters, acrylic acid copolymers, vinylpolymers, vinyl copolymers, polymers of vinyl alcohols, alkoxy polymers,polyethylene oxide polymers, polyethers, and mixtures thereof.
 9. Thedrug delivery system of claim 8 wherein said adhesive layer additionallycontains at least one member selected from the group consisting offillers, tableting excipients, lubricants, flavors, and dyes and whereinsaid drug/enhancer layer additionally contains at least one memberselected from the group consisting of tableting excipients, fillers,flavors, taste-masking agents, dyes, stabilizers, enzyme inhibitors, andlubricants.
 10. The drug delivery system of claim 9 wherein said bilesalt enhancer is a salt of a conjugate of a bile acid with taurine. 11.The drug delivery system of claim 10 wherein said hydrophilic polymercomprises a mixture of polyethylene oxide and polyacrylic acid.
 12. Thedrug delivery system of claim 11 wherein said first tissue is gingivaltissue.
 13. The drug delivery system of claim 12 wherein saidglucagon-like insulinotropic peptide is a member selected from the groupconsisting of GLP-1(7-36)amide, precursors of GLP-1(7-36)amide,analogues of GLP-1(7-36)amide, and fragments of GLP-1(7-36)amide. 14.The drug delivery system of claim 13 wherein said glucagon-likeinsulinotropic peptide is GLP-1(7-36)amide.
 15. The drug delivery systemof claim 4 wherein said device of determined physical form is a matrixpatch.
 16. The drug delivery system of claim 15 wherein said organicsolvent is a member selected from the group consisting of C₂ alcohols,C₃ alcohols, C₃ diols, C₄ diols, DMSO, DMA, DMF,1-n-dodecyl-cyclazacyclo-heptan-2-olle, N-methyl pyrrlidone,N-(2-hydroxyethyl) pyrrolidone, triacetin, propylene carbonate, dimethylisosorbide, and mixtures thereof; said cell-envelope disorderingcompound is a member selected from the group consisting of isopropylmyristate, methyl laurate, oleic acid, oleyl alcohol, glycerolmonoleate, glycerol dioleate, glycerol trioleate, glycerol monostearate,glycerol monolaurate, propylene glycol monolaurate, sodium dodecylsulfate, sorbitan esters and mixtures thereof; and said bile salt is asteroidal detergent selected from the group consisting of natural saltsof cholanic acid, synthetic salts of cholanic acids and mixturesthereof.
 17. The drug delivery system of claim 16 wherein saidglucagon-like insulinotropic peptide is a member selected from the groupconsisting of GLP-1(7-36)amide, precursors of GLP-1(7-36)amide,analogues of GLP-1(7-36)amide, and fragments of GLP-1(7-36)amide. 18.The drug delivery system of claim 17 wherein said glucagon-likeinsulinotropic peptide is GLP-1(7-36)amide.
 19. The drug delivery systemof claim 4 wherein said device of determined physical form is a liquidreservoir patch and wherein said drug composition is contained in saidreservoir.
 20. The drug delivery system of claim 19 wherein said organicsolvent is a member selected from the group consisting of C₂ alcohols,C₃ alcohols, C₃ diols, C₄ diols, DMSO, DMA, DMF,1-n-dodecyl-cyclazacyclo-heptan-2-one, N-methyl pyrrlidone,N-(2-hydroxyethyl) pyrrolidone, triacetin, propylene carbonate, dimethylisosorbide, and mixtures thereof; said cell-envelope disorderingcompound is a member selected from the group consisting of isopropylmyristate, methyl laurate, oleic acid, oleyl alcohol, glycerolmonoleate, glycerol dioleate, glycerol trioleate, glycerol monostearate,glycerol monolaurate, propylene glycol monolaurate, sodium dodecylsulfate, sorbitan esters, and mixtures thereof; and said bile salt is asteroidal detergent selected from the group consisting of natural saltsof cholanic acid, synthetic salts of cholanic acid, and mixturesthereof.
 21. The drug delivery system of claim 20 wherein saidglucagon-like insulinotropic peptide is a member selected from the groupconsisting of GLP-1(7-36)amide, precursors of GLP-1(7-36)amide,analogues of GLP-1(7-36)amide, and fragments of GLP-1(7-36)amide. 22.The drug delivery system of claim 21 wherein said glucagon-likeinsulinotropic peptide is GLP-1(7-36)amide.
 23. The drug delivery systemof claim 4 wherein said device of determined physical form is a troche.24. The drug delivery system of claim 23 wherein said glucagon-likeinsulinotropic peptide is a member selected from the group consisting ofGLP-1(7-36)amide, GLP-1(7-36)amide precursors, GLP-1(7-36)amideanalogues, and GLP-1(7-36)amide fragments thereof.
 25. The drug deliverysystem of claim 24 wherein said glucagon-like insulinotropic peptide isGLP-1(7-36)amide.
 26. The drug delivery system of claim 1 wherein saidformulation is in free form for application to said buccal mucosa and isa member selected from the group consisting of a gel, gum, cream, andointment.
 27. The drug delivery system of claim 26 wherein saidpenetration enhancer is a member selected from the group consisting oforganic solvents, a cell-envelope disordering compounds, steroidaldetergents, bile salts, chelators, surfactants, non-surfactants, fattyacids, and mixtures thereof.
 28. The drug delivery system of claim 27wherein said organic solvent is a member selected from the groupconsisting of C₂ alcohols, C₃ alcohols, C₃ diols, C₄ diols, DMSO, DMA,DMF, 1-n-dodecyl-cyclazacyclo-heptan-2-one, N-methyl pyrrlidone,N-(2-hydroxyethyl) pyrrolidone, triacetin, propylene carbonate dimethylisosorbide, and mixtures thereof; said cell-envelope disorderingcompound is a member selected from the group consisting of isopropylmyristate, methyl laurate, oleic acid, oleyl alcohol, glycerolmonoleate, glycerol dioleate, glycerol trioleate, glycerol monostearate,glycerol monolaurate, propylene glycol monolaurate, sodium dodecylsulfate, sorbitan esters, and mixtures thereof; and said bile salt is asteroidal detergent selected from the group consisting of natural saltsof cholanic acid, synthetic salts of cholanic acid, and mixturesthereof.
 29. The drug delivery system of claim 28 wherein saidglucagon-like insulinotropic peptide is a member selected from the groupconsisting of GLP-1(7-36)amide, precursors of GLP-1(7-36)amide,analogues of GLP-1(7-36)amide, and fragments of GLP-1(7-36)amide. 30.The drug delivery system of claim 28 wherein said glucagon-likeinsulinotropic peptide is GLP-1(7-36)amide.
 31. The drug delivery systemof claim 1 wherein said drug composition further comprises a sulfonylurea.
 32. A method of delivering a glucagon-like insulinotropic peptidefor transbuccal drug delivery to an individual's buccal mucosacomprising bringing said buccal mucosa into contact with a deliverysystem comprising:(a) a drug composition comprising an effective amountof said glucagon-like insulinotropic peptide and an effective amount ofa permeation enhancer for enhancing permeation of said glucagon-likeinsulinotropic peptide through said buccal mucosa; and (b) means formaintaining said drug composition in a drug transferring relationshipwith said buccal mucosa, wherein said drug composition and saidmaintaining means are combined in a single formulation; and retainingsaid delivery system in contact with said mucosa for a time sufficientto delivery an effective amount of said peptide to said individual. 33.The method of claim 32 wherein said system comprises a device ofdetermined physical form.
 34. The method of claim 33 wherein said deviceof determined physical form is a member selected from the groupconsisting of a patch and a tablet, and wherein said maintaining meansis an adhesive.
 35. The method of claim 34 wherein said permeationenhancer is a member selected from the group consisting of cell envelopedisordering compounds, solvents, steroidal detergents, bile salts,chelators, surfactants, non-surfactants, fatty acids, and mixturesthereof.
 36. The method of claim 35 wherein said device of determinedphysical form is a tablet.
 37. The method of claim 36 wherein saidtablet comprises an adhesive layer comprising a hydrophilic polymerhaving one surface adapted to contact a first tissue of the oral cavityand adhere thereto when wet and an opposing surface in contact with andadhering to an adjacent drug/enhancer layer comprising said permeationenhancer and said glucagon-like insulinotropic peptide, saiddrug/enhancer layer adapted to contact and be in drug transferrelationship with said buccal mucosa when said adhesive layer contactsand adheres to said first tissue.
 38. The method of claim 37 whereinsaid permeation enhancer comprises a bile salt, wherein said bile saltis a steroidal detergent selected from the group consisting of naturalsalts of cholanic acid, synthetic salts of cholanic acid, and mixturesthereof.
 39. The method of claim 38 wherein said hydrophilic polymercomprises at least one member selected from the group consisting ofhydroxypropyl cellulose, hydroxypropyl methylcellulose,hydroxyethylcellulose, ethylcellulose, carboxymethyl cellulose, dextran,gaur-gum, polyvinyl pyrrolidone, pectins, starches, gelatin, casein,acrylic acid polymers, polymers of acrylic acid esters, acrylic acidcopolymers, vinyl polymers, vinyl copolymers, polymers of vinylalcohols, alkoxy polymers, polyethylene oxide polymers, polyethers, andmixtures thereof.
 40. The method of claim 39 wherein said adhesive layeradditionally contains one or more members selected from the groupconsisting of fillers, tableting excipients, lubricants, flavors, anddyes and wherein said drug/enhancer layer additionally contains one ormembers selected from the group consisting of tableting excipients,fillers, flavors, taste-masking agents, dyes, stabilizers, enzymeinhibitors, and lubricants.
 41. The method of claim 40 wherein said bilesalt enhancer is a salt of a conjugate of a bile acid with taurine. 42.The method of claim 40 wherein said hydrophilic polymer comprises amixture of polyethylene oxide and polyacrylic acid.
 43. The method ofclaim 42 wherein said first tissue is gingival tissue.
 44. The method ofclaim 43 wherein said glucagon-like insulinotropic peptide is a memberselected from the group consisting of GLP-1(7-36)amide precursors ofGLP-1(7-36)amide, analogues of GLP-1(7-36)amide, and fragments ofGLP-1(7-36)amide.
 45. The method of claim 44 wherein said glucagon-likeinsulinotropic peptide is GLP-1(7-36)amide.
 46. The method of claim 35wherein said device of determined physical form is a matrix patch. 47.The method of claim 46 wherein said organic solvent is a member selectedfrom the group consisting of C₂ alcohols, C₃ alcohols, C₃ diols, C₄diols, DMSO, DMA, DMF, 1-n-dodecyl-cyclazacyclo-heptan-2-one. N-methylpyrrlidone, N-(2-hydroxyethyl) pyrrolidone, triacetin, propylenecarbonate, dimethyl isosorbide and mixtures thereof; said cell-envelopedisordering compound is a member selected from the group consisting ofisopropyl myristate, methyl laurate, oleic acid, oleyl alcohol, glycerolmonoleate, glycerol dioleate, glycerol trioleate, glycerol monostearate,glycerol monolaurate, propylene glycol monolaurate, sodium dodecylsulfate, sorbitan esters, and mixtures thereof; and said bile salt is asteroidal detergent selected from the group consisting of natural saltsof cholanic acid, synthetic salts of cholanic acids and mixturesthereof.
 48. The method of claim 47 wherein said glucagon-likeinsulinotropic peptide is a member selected from the group consisting ofGLP-1(7-36)amide, precursors of GLP-1(7-36)amide, analogues ofGLP-1(7-36)amide, and fragments of GLP-1(7-36)amide.
 49. The method ofclaim 48 wherein said glucagon-like insulinotropic peptide isGLP-1(7-36)amide.
 50. The method of claim 35 wherein said device ofdetermined physical form is a liquid reservoir patch and wherein saiddrug composition is contained in said reservoir.
 51. The method of claim50 wherein said organic solvent is a member selected from the groupconsisting of C₂ alcohols, C₃ alcohols, C₃ diols, C₄ diols, DMSO, DMA.DMF, 1-n-dodecyl-cyelazacyelo-heptan-2-one, N-methyl pyrrlidone,N-(2-hydroxyethyl) pyrrolidone, triacetin, propylene carbonate dimethylisosorbide and mixtures thereof; said cell-envelope disordering compoundis a member selected from the group consisting of isopropyl myristate,methyl laurate, oleic acid, oleyl alcohol, glycerol monoleate, glyceroldioleate, glycerol trioleate, glycerol monostearate, glycerolmonolaurate, propylene glycol monolaurate, sodium dodecyl sulfate,sorbitan esters, and mixtures thereof; and said bile salt is a steroidaldetergent selected from the group consisting of natural salts ofcholanic acid, synthetic salts of cholanic acid, and mixtures thereof.52. The method of claim 51 wherein said glucagon-like insulinotropicpeptide is a member selected from the group consisting ofGLP-1(7-36)amide, precursors of GLP-1(7-36)amide, analogues ofGLP-1(7-36)amide, and fragments of GLP-1(7-36)amide.
 53. The method ofclaim 52 wherein said glucagon-like insulinotropic peptide isGLP-1(7-36)amide.
 54. The method of claim 35 wherein said device ofdetermined physical form is a troche.
 55. The method of claim 54 whereinsaid glucagon-like insulinotropic peptide is a member selected from thegroup consisting of GLP-1(7-36)amide, precursors of GLP-1(7-36)amide,analogues of GLP-1(7-36)amide, and fragments of GLP-1(7-36)amide. 56.The method of claim 55 wherein said glucagon-like insulinotropic peptideis GLP-1(7-36)amide.
 57. The method of claim 32 wherein said formulationis in free form for application to said buccal mucosa and is a memberselected from the group consisting of a gel, gum, cream, and ointment.58. The method of claim 57 wherein said penetration enhancer is a memberselected from the group consisting of an organic solvents, cell-envelopedisordering compounds, steroidal detergents, bile salts, chelators,surfactants, non-surfactants, fatty acids, and mixtures thereof.
 59. Themethod of claim 58 wherein said organic solvent is a member selectedfrom the group consisting of C₂ alcohols, C₃ alcohols, C₃ diols, C₄diols, DMSO, DMA, DMF, 1-n-dodecyl-cyclazacyclo-heptan-2-one, N-methylpyrrlidone, N-(2-hydroxyethyl) pyrrolidone, triacetin, propylenecarbonate, dimethyl isosorbide, and mixtures thereof; said cell-envelopedisordering compound is a member selected from the group consisting ofisopropyl myristate, methyl laurate, oleic acid, oleyl alcohol, glycerolmonoleate, glycerol dioleate, glycerol trioleate, glycerol monostearate,glycerol monolaurate, propylene glycol monolaurate, sodium dodecylsulfate, sorbitan esters, and mixtures thereof; and said bile salt is asteroidal detergent selected from the group consisting of natural saltsof cholanic acid, synthetic salts of cholanic acids and mixturesthereof.
 60. The method of claim 59 wherein said glucagon-likeinsulinotropic peptide is a member selected from the group consisting ofGLP-1(7-36)amide, precursors of GLP-1(7-36)amide, analogues ofGLP-1(7-36)amide, and fragments of GLP-1(7-36)amide.
 61. The method ofclaim 60 wherein said glucagon-like insulinotropic peptide isGLP-1(7-36)amide.
 62. The method of claim 32 wherein said drugcomposition further comprises a sulfonyl urea.